1. Field of the Invention
The present invention relates generally to medical devices, systems, and methods to treat disease. More particularly, the present invention relates to methods to treat hypertension by delivering agents to reduce hyperactive sympathetic nerve activity in the adventitia of arteries and/or veins that lead to the kidneys.
Hypertension, or high blood pressure, affects an estimated 30-40% of the world's adult population. Renal, or renovascular, hypertension can be caused by hypoperfusion of the kidneys due to a narrowing of the renal arteries. The kidneys respond by giving off hormones that signal the body to retain salt and water, causing the blood pressure to rise. The renal arteries may narrow due to arterial injury or atherosclerosis. Despite effective drug regimens to regulate the renin-angiotensin-aldosterone pathway or to remove excess fluid from the body and reduce blood pressure, some 20-30% of patients with hypertension suffer from resistant forms of the disease.
Resistant hypertension is a common clinical problem, caused when a patient is unable to control high blood pressure by systemic medication alone. Resistant hypertension is especially a problem in old and obese people. Both of these demographics are growing. While symptoms are not obvious in these patients, cardiovascular risk is greatly increased when they are unable to control their blood pressure.
Hypertension is also caused by hyperactive renal sympathetic nerves. Renal sympathetic efferent and afferent nerves run generally longitudinally along the outside of arteries leading from the aorta to the kidneys. These nerves are critically important in the initiation and maintenance of systemic hypertension. It has been shown that by severing these nerves, blood pressure can be reduced. Exemplary experiments have shown that denervation of the renal sympathetic nerves in rats with hyperinsulinemia-induced hypertension would reduce the blood pressure to normotensive levels as compared to controls [Huang W-C, et al. Hypertension 1998; 32:249-254].
Percutaneous or endoscopic interventional procedures are very common in the United States and other countries around the world. Intravascular catheter systems are used for procedures such as balloon angioplasty, stent placement, atherectomy, retrieval of blood clots, photodynamic therapy, and drug delivery. All of these procedures involve the placement of long, slender tubes known as catheters into arteries, veins, or other lumens of the body in order to provide access to the deep recesses of the body without the necessity of open surgery.
In cases where renal arterial occlusion is causing hypertension that cannot be controlled with medication, another potential therapy includes balloon angioplasty of the renal artery. In rare cases, surgical bypass grafting may be considered as a therapeutic alternative. While renal angioplasty can be effective in reducing blood pressure, angioplasty is plagued with resulting restenosis due to elastic recoil, dissection, and neointimal hyperplasia. Renal stents may improve the result, but also lead to restenosis or renarrowing of the artery due to neointimal hyperplasia.
While renal denervation had been performed with surgical methods in the past, more recently a catheter-based therapy to heat and destroy the nerves from within the renal artery using radio-frequency ablation has been studied. A human trial of the RF-ablation catheter method has also been performed, with reported reduction in blood pressure in patients enrolled in the catheter treatment arm of the study [Krum H, et al. Lancet 2009; 373(9671):1228-1230].
While the use of catheter-based radiofrequency (RF) denervation appears to have a therapeutic effect, it is unknown what long-term implications will arise from the permanent damage caused to the vessel wall and nerves by the RF procedure. Radiofrequency energy denervates the vessel by creating heat in the vessel wall. The RF probe contacts the inner lining of the artery and the RF energy is transmitted through the tissue.
Anti-hypertension therapies can be problematic in a number of respects. First, hypertension is, for the most part, an asymptomatic disease. Patients can lack compliance to medicinal regimens due to their perceived lack of symptoms. Second, even for patients that are highly compliant to drug therapy, their target blood pressure may not be reached, with little to no recourse but for intervention. Third, when intervention is taken (usually in the form of renal angioplasty and/or stenting), the long-term effects can include restenosis, progression of chronic kidney disease, and ultimately kidney failure, because angioplasty leads to activation of an injury cascade that causes fibrosis and remodeling of the target artery. Fourth, surgical techniques to bypass or denervate renal arteries are radical and can lead to a number of surgical complications. And fifth, it is unknown whether RF denervation of the artery will lead to further exacerbation of stenotic plaques, whether it is compatible with arteries in which stents have been placed, whether the energy transmission through thick plaques or fibrous intima will be enough to effect the underlying nerves procedure will work if the RF probe is in contact with a thick plaque in the majority of patients, or whether the effective deadening of not only nerves, but the smooth muscle in the arterial wall also, may lead to reactive hypervascular formation of the vasa vasorum and necrotizing plaques that, if ruptured, would result in acute kidney ischemia or chronic kidney disease. Thus, systems and protocols which are designed to produce sympathetic denervation with RF energy or surgical dissection are limited in their applicability across the breadth of hypertensive disease, or they may create new vascular complications that were not inherent to the underlying disease.
Neurotoxic agents like botulinum toxin, β-bungarotoxin (and other snake venom toxins), tetanus toxin, and α-latrotoxin, have been used or proposed for use in many surgical techniques to block nerves, reduce muscle activity or paralyze muscles. Neuromuscular blocking agents like tubocurarine, alcuronium, pipecuronium, rocuronium, pancuronium, vecuronium (and other curare-like drugs, derived originally from paralytic darts and arrows of South American tribes) have also been used to induce paralysis by competing for cholinergic receptors at the motor end-plate. The curare-like agents are short acting in comparison to the toxins. For example, botulinum toxin (which can be one of 7 different serologically distinct types, from type A to type G) have been used and is FDA approved to treat strabismus, blepharospasm, hemifacial spasm, improvement of moderate to severe frown lines (cosmetic), and for the treatment of excessive underarm sweating. Each of these uses for botulinum toxin has shown treatment effect ranging from several months to more than a year.
The lethal dose of botulinum toxin is approximately 1 ng/kg as determined by experiments in mice. Currently available forms of botulinum toxin, MYOBLOC™ and BOTOX® have specific activity of 70 to 130 U/ng and approximately 20 U/ng, respectively. One unit (1 U) is the amount of toxin found to cause death in 50% of mice tested 72 hours after intraperitoneal administration. MYOBLOC™ is available in 2500, 5000, or 10000 U vials and is prescribed for dosage totaling 2500 to 5000 U for the treatment of cervical dystonia. BOTOX® is available in 100 U per vial and is prescribed in dosages of 200-300 U for cervical dystonia, 50-75 U for axillary hyperhidrosis, or 12 U spread across 6 injections for blepharospasm. Active botulinum toxin is made up of a heavy chain and light chain with a total mass of 150 kDa; therefore, each 1 ng of active material contains approximately 4 billion active toxin molecules.
Current antihypertensive drugs typically modulate blood pressure by interrupting the renin-angiotensin-aldosterone axis or by acting as a diuretic. An earlier generation of antihypertensive agents had modes of action to directly impair the renal nervous system. Agents like guanethidine, guanacline, and bretylium tosylate would modulate hypertension by preventing release of norepinephrine (also known as noradrenaline) from sympathetic nerve terminals. With guanethidine, sympathectomy is accomplished by interfering with excitatory vesicular release and by replacing norepinephrine in synaptic vesicles. Sympathetic nerve failure has been previously demonstrated in rats and hamsters, but not humans, possibly because guanethidine was typically delivered systemically and the high local concentrations required to induce sympathetic denervation in humans would come at the risk of extremely undesirable systemic side effects. The use of guanethidine to create functional denervation in rodents is considered permanent, with no evidence of reinnervation of tissues for as long as 63 weeks after treatment in rats. In high doses, guanethidine inhibits mitochondrial respiration and leads to neuron death. Importantly for this invention, guanethidine can be used to create local denervation in a dose-dependent manner and without far-field effects. This has been seen in an experiment comparing guanethidine injection into one hindquarter of a hamster and compared to a control injection on the contralateral side, performed by Demas and Bartness, J Neurosci Methods 2001. This is an advantage for the use of the agent to localize the effect to a specific renal artery without diffusion beyond the renal sympathetic ganglion to the spinal cord or other nervous systems. Also of interest to this invention is the published observation that guanethidine selectively destroys postganglionic noradrenergic neurons (thus reducing norepinephrine) while sparing dopaminergic fibers and nonneural catecholamine-secreting cells. It is this high level of specificity for which guanethidine has been chosen as a useful therapy. Finally, guanethidine was approved by FDA for use as a systemic antihypertensive agent due to its ability to block sympathetic function, but has not been approved for local administration to cause long-term or permanent denervation.
Locally delivered guanethidine has produced localized sympathectomy in hamster hindquarters, as observed by Demas and Bartness, 2001. In a series of 10 to 20 unilateral injections of 2 microliters each containing 5 to 10 micrograms of guanethidine per microliter, into the inguinal adipose tissue of hamsters, compared to similar injections of placebo into the contralateral inguinal adipose tissue, functional sympathectomy of one side versus the other was seen with at least 200 micrograms of delivery, whether spread across 10 or 20 injections of 2 microliters each. The result was determined in this case by measuring the norepinephrine content of the tissue 2 weeks after delivery, with substantial reduction in the side that had received guanethidine versus the control (placebo) side.
Guanethidine has the chemical name Guanidine, [2-(hexahydro-1(2H)-azocinyl)ethyl]-, and is often supplied in the sulfate form, guanethidine sulfate or guanethidine monosulfate (CAS 645-43-2) with chemical name Guanidine, [2-(hexahydro-1(2H)-azocinyl)ethyl]-, sulfate (1:1). Guanethidine has been marketed under the trade name Ismelin.
Other agents have been shown to create partial or complete sympathectomy as well. These include immunosympathectomy agent anti-nerve growth factor (anti-NGF); auto-immune sympathectomy agents anti-dopamine beta-hydroxylase (anti-DβH) and anti-acetylcholinesterase (anti-AChe); chemical sympathectomy agents 6-hydroxyldopamine (6-OHDA), bretylium tosylate, guanacline, and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4); and immunotoxin sympathectomy agents OX7-SAP, 192-SAP, anti-dopamine beta-hydroxylase saporin (DBH-SAP), and anti-dopamine beta-hydroxylase immunotoxin (DHIT). A full description of these agents is found in Picklo M J, J Autonom Nerv Sys 1997; 62:111-125. Phenol and ethanol have also been used to produce chemical sympathectomy and are also useful in the methods of this invention. Other sympatholytic agents include alpha-2-agonists such as clonidine, guanfacine, methyldopa, guanidine derivatives like betanidine, guanethidine, guanoxan, debrisoquine, guanoclor, guanazodine, guanoxabenz and the like; imadazoline receptor agonists such as moxonidine, relmenidine and the like; ganglion-blocking or nicotinic antagonists such as mecamylamine, trimethaphan and the like; MAOI inhibitors such as pargyline and the like; adrenergic uptake inhibitors such as rescinnamine, reserpine and the like; tyrosine hydroxylase inhibitors such as metirosine and the like; alpha-1 blockers such as prazosin, indoramin, trimazosin, doxazosin, urapidil and the like; non-selective alpha blockers such as phentolamine and the like; serotonin antagonists such as ketanserin and the like; and endothelin antagonists such as bosentan, ambrisentan, sitaxentan, and the like.
Additionally, agents that sclerose nerves can be used to create neurolysis or sympatholysis. Sclerosing agents that lead to the perivascular lesioning of nerves include quinacrine, chloroquine, sodium tetradecyl sulfate, ethanolamine oleate, sodium morrhuate, polidocanol, phenol, ethanol, or hypertonic solutions.
Renal sympathetic nerve activity leads to the production of norepinephrine. It has been well established that renal sympathectomy (also known as renal artery sympathectomy or renal denervation) reduces norepinephrine buildup in the kidney. This has been measured by studies that involved surgical denervation of the renal artery, published by Connors in 2004 for pigs, Mizelle in 1987 for dogs, and Katholi in 1981 for rats. In fact, it has been shown that surgical denervation of one renal artery with sham surgery on the contralateral renal artery results in reductions of approximately 90% or more in kidney norepinephrine content on the denervated side compared to the control side. This evidence of denervation is therefore used as a surrogate to test denervation methods in large animals like pigs, since these animals do not develop essential hypertension normally. Further evidence of the link between denervation and norepinephrine buildup has been presented in norepinephrine spillover from the kidney, measured in the renal vein outflow blood [as reported by Krum et al, Lancet 2009]. Further linkage has been made between the ability to reduce renal norepinephrine in large animal models (such as porcine models) indicating the ability to reduce blood pressure in hypertensive human patients.
Complete sympathectomy of the renal arteries remains problematic due to the side effects inherent with reducing blood pressure below normal levels. Over the past 30 years, an ongoing debate has taken place around the presence and impact of a “J-curve” when relating the reduction of hypertension to therapeutic benefit [Cruickshank J, Current Cardiology Reports 2003; 5:441-452]. This debate has highlighted an important point in the treatment of hypertension: that while reduction in blood pressure may reduce cardiovascular morbidity and mortality rates, too great a reduction leads to a reversal in benefit. With surgical sympathectomy, the renal efferent and afferent nerves are completely removed, so there is no ability to “titrate” the amount of sympathectomy for a given patient. An improved method is proposed here for a therapy that can be titrated to the needs of the individual patient with adventitial delivery of neurodegenerative or sympatholytic agents capable of creating dose-dependent sympathectomy. Given appropriate dose titration, therapy can be tailored to reach the bottom of the J-curve without overshooting and leading to hypotensive effects.
For all of these reasons, it would be desirable to provide additional and improved methods and kits for the adventitial/perivascular delivery of neurotoxic, sympatholytic, sympathetic nerve blocking agents or neuromuscular blocking agents (together with other agents that can modulate nerve function, neuromodulating agents) to accomplish biological and reversible denervation while not creating injury to the blood vessel or aggravating the underlying vascular disease. In particular, it would be beneficial to provide methods which specifically target therapeutic concentrations of the neuromodulating agents into the adventitia and perivascular tissue, where the sympathetic efferent and afferent nerves are located. It would be further beneficial if the methods could efficiently deliver the drugs into the targeted tissue and limit or avoid the loss of drugs into the luminal blood flow. It would be further beneficial if the methods could enhance the localization of neuromodulating agents in the adventitia and peri-adventitia, avoiding diffusion of agents to surrounding organs or nerves. It would be still further beneficial if the persistence of such therapeutic concentrations of the neuromodulating agents in the tissue were also increased, particularly in targeted tissues around the sympathetic nerves, including the adventitial tissue surrounding the blood vessel wall. Additionally, it would be beneficial to increase the uniformity of neuromodulating agent delivery over the desired treatment zone. Still further, it would be desirable if the tissue region or treatment zone into which the neuromodulating agent is delivered could be predicted and tracked with the use of visual imaging and positive feedback to an operating physician. At least some of these objectives will be met by the inventions described hereinafter.
2. Description of the Background Art
The following references are pertinent to intravascular and intraluminal drug delivery: O. Varenne and P. Sinnaeve, “Gene Therapy for Coronary Restenosis: A Promising Strategy for the New Millenium?” Current Interventional Cardiology Reports, 2000, 2: 309-315. B. J. de Smet, et. al., “Metalloproteinase Inhibition Reduces Constrictive Arterial Remodeling After Balloon Angioplasty: A Study in the Atherosclerotic Yucatan Micropig.” Circulation, 2000, 101: 2962-2967. A. W. Chan et. al., “Update on Pharmacology for Restenosis,” Current Interventional Cardiology Reports, 2001, 3: 149-155. Braun-Dullaeus R C, Mann M J, Dzau V J. Cell cycle progression: new therapeutic target for vascular proliferative disease. Circulation. 1998; 98(1):82-9. Gallo R, Padurean A, Jayaraman T, Marx S, Merce Roque M, Adelman S, Chesebro J, Fallon J, Fuster V, Marks A, Badimon J J. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation. 1999; 99:2164-2170 Herdeg C, Oberhoff M, Baumbach A, Blattner A, Axel D I, Schroder S, Heinle H, Karsch K R. Local paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo. J Am Coll Cardiol 2000 June; 35(7):1969-76. Ismail A, Khosravi H, Olson H. The role of infection in atherosclerosis and coronary artery disease: a new therapeutic target. Heart Dis. 1999; 1(4):233-40. Lowe H C, Oesterle S N, Khachigian L M. Coronary in-stent restenosis: Current status and future strategies. J Am Coll Cardiol. 2002 Jan. 16; 39(2):183-93. Fuchs S, Komowski R, Leon M B, Epstein S E. Anti-angiogenesis: A new potential strategy to inhibit restenosis. Intl J Cardiovasc Intervent. 2001; 4:3-6. Kol A, Bourcier T, Lichtman A H, and Libby P. Chlamydial and human heat shock protein 60 s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Invest. 103:571-577 (1999). Farsak B, Vildirir A, Akyon Y, Pinar A, Oc M, Boke E, Kes S, and Tokgozogclu L. Detection of Chlamydia pneumoniae and Helicobacter pylori DNA in human atherosclerotic plaques by PCR. J Clin Microbiol 2000; 38(12):4408-11 Grayston J T. Antibiotic Treatment of Chlamydia pneumoniae for secondary prevention of cardiovascular events. Circulation. 1998; 97:1669-1670. Lundemose A G, Kay J E, Pearce J H. Chlamydia trachomatis Mip-like protein has peptidyl-prolyl cis/trans isomerase activity that is inhibited by FK506 and rapamycin and is implicated in initiation of chlamydial infection. Mol Microbiol. 1993; 7(5):777-83. Muhlestein J B, Anderson J L, Hammond E H, Zhao L, Trehan S, Schwobe E P, Carlquist J F. Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation. 1998; 97:633-636. K. P. Seward, P. A. Stupar and A. P. Pisano, “Microfabricated Surgical Device,” U.S. application Ser. No. 09/877,653, filed Jun. 8, 2001. K. P. Seward and A. P. Pisano, “A Method of Interventional Surgery,” U.S. application Ser. No. 09/961,079, filed Sep. 20, 2001. K. P. Seward and A. P. Pisano, “A Microfabricated Surgical Device for Interventional Procedures,” U.S. application Ser. No. 09/961,080, filed Sep. 20, 2001. K. P. Seward and A. P. Pisano, “A Method of Interventional Surgery,” U.S. application Ser. No. 10/490,129, filed Mar. 11, 2003.
The following references are pertinent to renal denervation therapy to reduce hypertension: Calhoun D A, et al, “Resistant Hypertension: Diagnosis, Evaluation and Treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research,” Hypertension 2008; 51:1403-1419. Campese V M, Kogosov E, “Renal Afferent Denervation Prevents Hypertension in Rats with Chronic Renal Failure,” Hypertension 1995; 25:878-882. Ciccone C D and Zambraski E J, “Effects of acute renal denervation on kidney function in deoxycorticosterone acetate-hypertensive swine,” Hypertension 1986; 8:925-931. Connors B A, et al, “Renal nerves mediate changes in contralateral renal blood flow after extracorporeal shockwave lithotripsy,” Nephron Physiology 2003; 95:67-75. DiBona G F, “Nervous Kidney: Interaction between renal sympathetic nerves and the renin-angiotensin system in the control of renal function,” Hypertension 2000; 36:1083-1088. DiBona G F, “The Sympathetic Nervous System and Hypertension: Recent Developments,” Hypertension 2004; 43; 147-150. DiBona G F and Esler M, “Translational Medicine: The Antihypertensive Effect of Renal Denervation,” American Journal of Physiology—Regulatory, Integrative and Comparative Physiology. 2010 February; 298(2):R245-53. Grisk O, “Sympatho-renal interactions in the determination of arterial pressure: role in hypertension,” Experimental Physiology 2004; 90(2):183-187. Huang W-C, Fang T-C, Cheng J-T, “Renal denervation prevents and reverses hyperinsulinemia-induced hypertension in rats,” Hypertension 1998; 32:249-254. Krum H, et al, “Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study,” Lancet 2009; 373(9671):1228-1230. Joles J A and Koomans H A, “Causes and Consequences of Increased Sympathetic Activity on Renal Disease,” Hypertension 2004; 43:699-706. Katholi R E, Winternitz S R, Oparil S, “Role of the renal nerves in the pathogenesis of one-kidney renal hypertension in the rat,” Hypertension 1981; 3:404-409. Mizelle H L, et al, “Role of renal nerves in compensatory adaptation to chronic reductions in sodium uptake,” Am. J. Physiol. 1987; 252(Renal Fluid Electrolyte Physiol. 21):F291-F298.
The following references are pertinent to neurotoxic or neuroblocking agents: Excerpt from Simpson L L, “Botulinum Toxin: a Deadly Poison Sheds its Negative Image,” Annals of Internal Medicine 1996; 125(7):616-617: “Botulinum toxin is being used to treat such disorders as strabismus, spasmodic torticollis, and loss of detrusor sphincter control. These disorders are all characterized by excessive efferent activity in cholinergic nerves. Botulinum toxin is injected near these nerves to block release of acetylcholine.” Clemens M W, Higgins J P, Wilgis E F, “Prevention of anastomotic thrombosis by Botulinum Toxin A in an animal model,” Plast Rectonstr Surg 2009; 123(1) 64-70. De Paiva A, et al, “Functional repair of motor endplates after botulinum neurotoxin type A poisoning: Biphasic switch of synaptic activity between nerve sprouts and their parent terminals,” Proc Natl Acad Sci 1999; 96:3200-3205. Morris J L, Jobling P, Gibbins I L, “Botulinum neurotoxin A attenuates release of norepinephrine but not NPY from vasoconstrictor neurons,” Am J Physiol Heart Circ Physiol 2002; 283:H2627-H2635. Humeau Y, Dousseau F, Grant N J, Poulain B, “How botulinum and tetanus neurotoxins block neurotransmitter release,” Biochimie 2000; 82(5):427-446. Vincenzi F F, “Effect of Botulinum Toxin on Autonomic Nerves in a Dually Innervated Tissue,” Nature 1967; 213:394-395. Carroll I, Clark J D, Mackey S, “Sympathetic block with botulinum toxin to treat complex regional pain syndrome,” Annals of Neurology 2009; 65(3):348-351. Cheng C M, Chen J S, Patel R P, “Unlabeled Uses of Botulinum Toxins: A Review, Part 1,” Am J Health-Syst Pharm 2005; 63(2):145-152. Fassio A, Sala R, Bonanno G, Marchi M, Raiteri M, “Evidence for calcium-dependent vesicular transmitter release insensitive to tetanus toxin and botulinum toxin type F,” Neuroscience 1999; 90(3):893-902. Baltazar G, Tomé A, Carvalho A P, Duarte E P, “Differential contribution of syntaxin 1 and SNAP-25 to secretion in noradrenergic and adrenergic chromaffin cells,” Eur J Cell Biol 2000; 79(12):883-91. Smyth L M, Breen L T, Mutafova-Yambolieva V N, “Nicotinamide adenine dinucleotide is released from sympathetic nerve terminals via a botulinum neurotoxin A-mediated mechanism in canine mesenteric artery,” Am J Physiol Heart Circ Physiol 2006; 290:H1818-H1825. Foran P, Lawrence G W, Shone C C, Foster K A, Dolly J O, “Botulinum neurotoxin C1 cleaves both syntaxin and SNAP-25 in intact and permeabilized chromaffin cells: correlation with its blockade of catecholamine release,” Biochemistry 1996; 35(8):2630-6. Demas G E and Bartness T J, “Novel Method for localized, functional sympathetic nervous system denervation of peripheral tissue using guanethidine,” Journal of Neuroscience Methods 2001; 112:21-28. Villanueva I, et al., “Epinephrine and dopamine colocalization with norepinephrine in various peripheral tissues: guanethidine effects,” Life Sci. 2003; 73(13)1645-53. Picklo M J, “Methods of sympathetic degeneration and alteration,” Journal of the Autonomic Nervous System 1997; 62:111-125. Nozdrachev A D, et al., “The changes in the nervous structures under the chemical sympathectomy with guanethidine,” Journal of the Autonomic Nervous System 1998; 74(2-3):82-85.
The following references are pertinent to self-assembling peptide hydrogel matrix, useful to extend pharmacokinetics as described in this invention: Koutsopoulos S, Unsworth L D, Nagai Y, Zhang S, “Controlled release of functional proteins through designer self-assembling peptide nanofiber hydrogel scaffold,” Proc Natl Acad Sci 2009; 106(12):4623-8. Nagai Y, Unsworth L D, Koutsopoulos S, Zhang S, “Slow release of molecules in self-assembling peptide nanofiber scaffold,” J Control Rel. 2006; 115:18-25. BD™ PURAMATRIX™ Peptide Hydrogel (Catalog No. 354250) Guidelines for Use, BD Biosciences, SPC-354250-G Rev 4.0. Erickson I E, Huang A H, Chung C, Li R T, Burdick J A, Mauck R L, Tissue Engineering Part A. online publication ahead of print. doi:10.1089/ten.tea.2008.0099. Henriksson H B, Svanvik T, Jonsson M, Hagman M, Horn M, Lindahl A, Brisby H, “Transplantation of human mesenchymal stems cells into intervertebral discs in a xenogeneic porcine model,” Spine 2009 Jan. 15; 34(2):141-8. Wang S, Nagrath D, Chen P C, Berthiaume F, Yarmush M L, “Three-dimensional primary hepatocyte culture in synthetic self-assembling peptide hydrogel,” Tissue Eng Part A 2008 February; 14(2):227-36. ThonhoffJR, Lou D I, Jordan P M, Zhao X, Wu P, “Compatibility of human fetal neural stem cells with hydrogel biomaterials in vitro,” Brain Res 2008 Jan. 2; 1187:42-51. Spencer N J, Cotanche D A, Klapperich C M, “Peptide- and collagen-based hydrogel substrates for in vitro culture of chick cochleae,” Biomaterials 2008 March; 29(8):1028-42. Yoshida D, Teramoto A, “The use of 3-D culture in peptide hydrogel for analysis of discoidin domain receptor 1-collagen interaction,” Cell Adh Migr 2007 April; 1(2):92-8. Kim M S, Yeon J H, Park JK, “A microfluidic platform for 3-dimensional cell culture and cell-based assays,” Biomed Microdevices 2007 February; 9(1):25-34. Misawa H, Kobayashi N, Soto-Gutierrez A, Chen Y, Yoshida A, Rivas-Carrillo J D, Navarro-Alvarez N, Tanaka K, Mild A, Takei J, Ueda T, Tanaka M, Endo H, Tanaka N, Ozaki T, “PuraMatrix facilitates bone regeneration in bone defects of calvaria in mice,” Cell Transplant 2006; 15(10):903-10. Yamaoka H, Asato H, Ogasawara T, Nishizawa S, Takahashi T, Nakatsuka T, Koshima I, Nakamura K, Kawaguchi H, Chung U I, Takato T, Hoshi K, “Cartilage tissue engineering using human auricular chondrocytes embedded in different hydrogel materials,” J Biomed Mater Res A 2006 July; 78(1):1-11. Bokhari M A, Akay G, Zhang S, Birch M A, “The enhancement of osteoblast growth and differentiation in vitro on a peptide hydrogel-polyHIPE polymer hybrid material,” Biomaterials 2005 September; 26(25):5198-208. Zhang S, Semino C, Ellis-Behnke R, Zhao X, Spirio L, “PuraMatrix: Self-assembling Peptide Nanofiber Scaffolds. Scaffolding in Tissue Engineering,” CRC Press, 2005. Davis M E, Motion J P, Narmoneva D A, Takahashi T, Hakuno D, Kamm R D, Zhang S, Lee R T, “Injectable self-assembling peptide nanofibers create intramyocardial microenvironments for endothelial cells,” Circulation 111: 442-450, 2005.
The following references are pertinent to carotid sinus syndrome (CSS) and adventitial denervation as a treatment option: Healey J, Connolly S J, Morillo C A, “The management of patients with carotid sinus syndrome: is pacing the answer,” Clin Auton Res 2004 October; 14 Suppl 1:80-6. Toorop R J, Schelting a M R, Bender M H, Charbon J A, Huige M C, “Effective surgical treatment of the carotid sinus syndrome,” J Cardiovasc Surg (Torino) 2008 Oct. 24. Toorop R J, Schelting a M R, Moll F L, “Adventitial Stripping for Carotid Sinus Syndrome,” Ann Vasc Surg 2009 Jan. 7.